Alterations in microsomal electron transport, oxidative N-demethylation and azo-dye cleavage in carbon tetrachloride and dimethylnitrosamine-induced liver injury

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Abstract
The effect of administration of carbon tetrachloride and dimethylnltrosamine in vivo on hepatic microsomal function related to drug metabolism was measured. The capacity of isolated microsomes to demethylate dimethylaniline was diminished during the first hr after carbon tetrachloride poisoning and during the second hr after dimethylnitrosamine poisoning. Thereafter the microsomes from carbon tetrachloride-poisoned livers showed a continuous decline in activity so that at 24 hr. there was little residual capacity to undertake demethylation. Microsomes from dimethylnitrosamine-poisoned animals were not different from controls at 24 hr. During the first 3 hr. there was a transient rise in the accumulation of the N-oxide intermediate in carbon tetrachloride-poisoned livers, with a subsequent fall to below control values. In dimethylnitrosamine poisoning there was a parallel decrease in N-oxide accumulation with decreased demethylation. In the latter part of the first 24 hr. the ratio of N-oxide accumulation to demethylation was increased in both instances. At 2 hr. after poisoning with either compound there was no evidence of altered NADPH2-dependent neotetrazolium reduction or lipid peroxidation. NADPH2-dependent azo-dye cleavage was decreased. There was no difference in microsomal cytochrome b5 content, but there was a decrease in the amount of cytochrome P-450. This latter change was correlated with the decreased capacity for NADPH2-dependent oxidative demethylation. It is suggested that dimethylnitrosamine is associated with a defect in microsomal NADPH2-dependent electron transport at the level of cytochrome P-450. In addition to affecting cytochrome P-450, carbon tetrachloride is associated with a second severe block involving the release of formaldehyde from the N-oxide intermediate.